Depression is among the most prevalent of all psychiatric disorders, accounting for over 20% of economic costs for all mental illness. An important public health priority is the identification of factors that both increase individuals'vulnerability to depression and hinder recovery from this disorder. Abnormalities in cardiac vagal control may confer vulnerability to depression. More specifically, two distinct abnormalities in cardiac vagal control may confer vulnerability: low vagal level (VL) usually measured in a resting state, and low vagal fluctuation (VF), usually measured in response to environmental demands. VL and VF are increasingly understood as independent predictors of physical and mental health outcomes. To date, mood disorders research has focused almost exclusively on VL, with results largely inconclusive as to its etiological and prognostic value. Early data from our laboratory suggests that depression is characterized by low VF and that VF may predict the subsequent course of clinically significant depression. The broad objective of this R21 exploratory research project is to investigate VF as a liability marker for depression. We will use a battery of previously-validated laboratory tasks to elicit VF in 60 outpatients diagnosed with current unipolar depression, 30 participants with a past diagnosis of unipolar depression, and 30 healthy non-psychiatric participants. VL and VF will be assessed via high-frequency heart period variability derived from the electrocardiogram. Participants will be followed longitudinally and reassessed at six months. The specific aims of this project are to examine: (1) whether depression vulnerability is associated cross-sectionally with reduced VF during and after experimental stressors;and (2) whether those depressed individuals who preserve dynamic VF during and after experimental stressors are more likely to recover from their disorder six months later. The investigators intend to use these R21 data as the foundation for a larger R01 research grant project that will examine VF with respect to: (a) psychiatric disorders other than MDD;(b) predicting outcome over longer periods (~3 years);(c) predicting outcome in a controlled treatment modality;and (d) potential antidepressant effects of VF modification. From a public health perspective, the hypothesis that depression risk is related to low VF is exciting because it suggests that easily acquired and potentially manipulable measures of heart rate variability could be used to assist in the early assessment of depression risk, and perhaps to develop interventions that operate directly upon the vagal pathway itself. PUBLIC HEALTH RELEVANCE: An important public health priority is the identification of factors that both increase individuals'vulnerability to depression and hinder recovery from this disorder. Abnormalities in cardiac vagal control may confer vulnerability to depression. This project will examine the hypothesis that depression risk is related to a lack of dynamic cardiac vagal control, which is potentially important because it suggests that easily acquired and potentially manipulable measures of heart rate variability could be used to assist in the early assessment of depression risk, and perhaps to develop interventions that operate directly upon the vagal pathway itself.